Breaking News: A New Hope for AML Patients!
The medical world is buzzing with excitement over the SAVE regimen, a groundbreaking treatment approach for acute myeloid leukemia (AML). This all-oral combination therapy, consisting of revumenib, decitabine/cedazuridine, and venetoclax, has shown remarkable response rates and minimal residual disease (MRD) negativity in newly diagnosed AML patients. However, there's a catch - myelosuppression and infectious complications remain major concerns.
According to the phase 1/2 SAVE trial, the regimen induced an impressive objective response rate (ORR) of 86% in patients with newly diagnosed AML. This included a complete remission (CR) rate of 76% and a CR with partial hematologic recovery (CRh) rate of 5%. All patients who achieved composite CR also tested negative for MRD at a sensitivity of 10-4 using multiparameter flow cytometry. Unfortunately, two early deaths occurred, and one patient withdrew consent, leaving us with some unanswered questions.
At a median follow-up of 9 months, the median duration of response (DOR) and overall survival (OS) were not yet reached, indicating potentially long-lasting remissions. The 12-month DOR and OS rates were 70% and 57%, respectively. The median event-free survival (EFS) also remained unattained, with a 12-month EFS rate of 50%.
In terms of safety, the most common adverse effects included vomiting, elevated liver enzymes, nausea, and electrolyte disturbances. Grade 3 or higher adverse events were predominantly febrile neutropenia, thrombocytopenia, neutropenia, bacteremia, and site-specific infections (lung and skin). Three grade 5 events were reported, including bacteremia and bronchopulmonary hemorrhage. Differentiation syndrome occurred in 19% of patients, with two cases being grade 3 or higher, but all resolved with steroid treatment.
Wei-Ying Jen, an assistant professor at The University of Texas MD Anderson Cancer Center, highlighted the promising activity of the all-oral combination in newly diagnosed AML patients with NPM1 mutations or KMT2A rearrangements. However, Jen expressed concern about the rate of infectious complications, emphasizing the need to optimize menin inhibitor combinations to improve the overall risk-benefit profile, especially in NPM1-mutated AML.
But here's where it gets controversial...
Menin, a scaffold protein, plays a crucial role in regulating gene expression. Its interaction with KMT2A is a critical dependency in KMT2A-rearranged or NPM1-mutated acute leukemias, leading to abnormal gene expression and leukemogenesis. Revumenib, a potent and selective small molecule inhibitor, targets this interaction.
In November 2024, the FDA approved revumenib for relapsed or refractory AML with a KMT2A translocation, and later, in October 2025, for relapsed or refractory AML with a susceptible NPM1 mutation.
The rationale behind the SAVE combination lies in improving response rates and reducing relapse risk. Single-agent revumenib has shown ORRs ranging from 43% to 60% in relapsed/refractory AML patients with KMT2A rearrangement or NPM1 mutation, but responses were short-lived. Hypomethylating agents combined with venetoclax are standard treatment for older or unfit AML patients, but relapse is still common. Preclinical data suggest that BCL-2 and menin inhibition could enhance survival outcomes.
The phase 1/2 SAVE trial enrolled patients with relapsed or refractory AML or mixed phenotype acute leukemia aged 12 years or older. The primary objectives were to evaluate safety, identify the maximum tolerated dose, and determine the recommended phase 2 dose (RP2D) in phase 1. In phase 2, the focus shifted to evaluating the regimen's efficacy in frontline and relapsed/refractory disease. Secondary objectives included OS, relapse-free survival, complete response duration, and MRD. Exploratory objectives centered on MRD at 10-5 and resistance mechanisms.
During the first cycle, a day 14 bone marrow assessment was performed. If bone marrow blasts were below 5%, revumenib was held after day 21. Revumenib monotherapy was then resumed as maintenance post-transplant for a planned duration of one year.
At the 2025 ASH Annual Meeting, Jen presented the outcomes of the newly diagnosed cohort. The median age was 70 years, with 52% of patients aged 70 or older. Most patients were female (71%), and almost a quarter had secondary AML (24%). Common comutations included NRAS/KRAS (19%), FLT3 (ITD, 5%; TKD, 14%), IDH1/2 (19%), and MDS-associated mutations in genes like ASCL1, BCOR, EZH2, SF3B1, STAG2, U2AF1, ZRSR2, and RUNX1 (43%).
The efficacy of the SAVE regimen varied based on genotype. In patients with NPM1 mutations, the ORR was 86%, with a CR/CRh rate of 79%. The CR rate was 71%, and the CRh rate was 7%. The CRp rate was 7% in this group. Most patients (86%) achieved MRD negativity 10-4 by multicolor flow cytometry. Two patients (10%) experienced early death. The median DOR and OS were not reached, with 12-month DOR and OS rates of 71% and 53%, respectively.
In patients with KMT2A rearrangements, the SAVE regimen induced an ORR of 86%, with a CR/CRh rate of 86%. The CR rate was also 86%, and 14% of patients were not evaluable. Again, 86% of patients achieved MRD negativity 10-4. The median DOR was not reached, with a 12-month DOR rate of 80%. The median OS was also unattained, with a 12-month OS rate of 69%.
Most patients achieved MRD negativity at the end of cycle 2, with clearance rates improving over time. Two patients did not clear NPM1 MRD and relapsed. In those who achieved CR/CRh, the median DOR was not reached. An estimated 70% of patients remained in remission at one year, and at a median follow-up of 9 months, the median OS and EFS had not been determined.
In terms of resistance mechanisms, a ddPCR assay was designed to identify eight MEN1 point mutations that confer resistance to revumenib. Synthetic gBlocks representing each mutation and wild-type controls were generated for assay development and optimization. However, there was false-positive detection of some variants at a low mutation burden, likely due to wild-type MEN1 gene binding.
At the time of relapse, MEN1 mutation testing was performed for two of the three relapse cases. One MEN1 M327B mutation was detected with a variant allele frequency of 17%. This mutation has been observed in vivo and in vitro with exposure to revumenib and other menin inhibitors. The emergent MEN1 mutation suggests that the combination regimen may not fully address this relapse mechanism, and further examination of other resistance mechanisms inherent to the combination is warranted.
So, what's your take on this groundbreaking treatment approach? Do you think the benefits outweigh the risks? Share your thoughts in the comments below!
